What happens when the ER goes wrong...ER STRESS!
Under normal physiological conditions, an equilibrium exists within the ER between protein load and folding capacity (Ozcan and Tabas 2012). If this homeostasis is perturbed due to factors such: * Increased protein synthesis * Accumulation of misfolded proteins * Alterations in calcium/redox balance of the ER A condition arises called the U'nfolded '''P'rotein 'R'esponse (UPR) sometimes known as the ER stress response (David and Peter 2007). To alleviate the disruption in ER homeostasis the cell has adapted this signalling pathway (Ozcan and Tabas 2012). The initial objectives of the UPR is to try and re-establish ER homeostasis by relieving ER stress through two major mechanisms (Ira and David 2011): # Increasing the folding capacity of the ER- This is achieved by gene expression of folding protein chaperones # Downregulating ER protein load- This achieved by inhibiting general protein translation and the promotion of degradation of misfolded proteins. The UPR signalling pathway is initiated by three ER membrane associated sensors (Kadowaki and Nishitoh 2013). These sensors detect the disruption in ER homeostasis a) IRE1 Pathway- Activated by dissociation of Binding Immunoglobulin Protein (BiP) from IRE. This enables the accumulated misfolded proteins to associate with BiP and become activated as shown in figure 11. Activated IRE1 induces cytosolic splicing of transcription factors that result in the induction of ER chaperones (Urano'' et al.'' 2000). b) ATF6 Pathway - Activated by dissociation of BiP in response to accumulation of misfolded proteins. This causes ATF6 to translocate to the Golgi where it is processed. The N terminal of the protein translocates to the nucleus where it induces a number of UPR genes, most notably ER chaperones [http://the-smooth-and-rough-endoplasmic-reticulum.wikia.com/wiki/References?venotify=created (Chen'' et al.2002)]. c) PERK Pathway- Activated by dissociation of BiP in response to accumulation of misfolded proteins. Activated PERK phosphorylates transcription factors that result in global reduction, resulting in reduced protein load to the ER, as shown in figure 11 [http://the-smooth-and-rough-endoplasmic-reticulum.wikia.com/wiki/References?venotify=created (Anne et al.'' 2000)] . If this stress is prolonged/severe the UPR ultimately initiates programmed cell death, known as Apoptosis. UPR mediated cell death may contribute to the pathogenesis of many diseases. '''Alzheimer’s disease Genetic studieshave shown that there are mutations in Amyloid-Beta precursor (APP). Mutations in the Presenilins P1 gene have been shown to interfere with the physiological functions of the UPR. This increases the likelihood of ER stress-induced cell death (Taiichi'' et al.'' 1999). Cell death of neurons play a vital role in the disease. Recent studies have indicated that in Alzheimer’s disease brain UPR is activated and the ER chaperone Grp78, which is an indicator of UPR is expressed in AD compared to the control (Hoozemans'' et al.'' 2005). Type 2 Diabetes ER stress mediated activation of JNK has been linked to insulin resistance through phosphorylating insulin receptor subrate-1 (IRS1) (Boden'' et al.'' 2008). ER stress in obesity is induced by the demand for protein synthesis when there are high levels of fatty acids (Ozcan and Tabas 2012). An example is Palmitate which has been shown to cause ER stress and activate the UPR in animal models Cancer High rates of growth and proliferation means that there is a requirement for cancer cells to have increased protein synthesis and folding in the ER. Also, some cancer cells express mutant proteins that cannot be correctly folded (Ozcan and Tabas 2012). This activates the UPR. When a tumour becomes malignant there is poor vascularisation which results in nutrient starvation and hypoxia. This leads to changes in the redox environment. These processes are all strong inducers of certain UPR pathways. In order to consolidate this information, here is a very useful YouTube video to watch https://www.youtube.com/watch?v=vy4m-fUOn9o